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US3296071A - Reducing blood sugar with 3-alkyl-5-alkoxymethylisoxazole - Google Patents

Reducing blood sugar with 3-alkyl-5-alkoxymethylisoxazole Download PDF

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US3296071A
US3296071A US284307A US28430763A US3296071A US 3296071 A US3296071 A US 3296071A US 284307 A US284307 A US 284307A US 28430763 A US28430763 A US 28430763A US 3296071 A US3296071 A US 3296071A
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methyl
alkyl
methoxymethylisoxazole
alkoxymethylisoxazole
oil
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John B Wright
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Pharmacia and Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • R and R are alkyl groups of 1-4 carbon atoms
  • n is an integer less than 3
  • MS is a metal salt.
  • Musante also discloses the reaction of ethoxyacetylacetone with hydroxylamine as giving 5-methyl-3-ethoxymethylisoxazole, as follows:
  • the starting l-alkoxy- 4-alkylbutane-2,4-diones such as methoxyacetylacetone, ethoxyacetylacetone, isopropoxyacetylacetone and sec-butoxyacetylacetone, are prepared by known methods from the appropriate ethylalkoxyacetate and alkylmethylketone in the presence of sodium ethoxide, according to the reaction:
  • R and R are alkyl groups containing 14 carbon atoms.
  • the exact schedule of administration in animals is determined individually according to the subjects age, weight, response to the medication and nature and severity of the condition being treated.
  • the exact schedule of administration in animals is determined individually according to the subjects age, weight, response to the medication and nature and severity of the condition being treated.
  • for use in reducing the blood sugar content for example, from about 25 to about 500 mg. of 3,5-disubstituted isoxazole can be administered orally as a single dose one to four times daily.
  • 3-alkyl-5-alkoxymethylisoxazoles as the sole active ingredient, other complementary ingredients can be included in the composition to secure advantageous combinations of properties especially adapted to individual situations in the treatment of the foregoing conditions.
  • other hypoglycemic agents such as tolbutamide, chlorpropamide, phenformin hydrochloride, mesoxalic acid, insulin, nicotinic acid, and the like can be included in the present formulations in amounts not exceeding and preferably less than those normally employed in single unit doses where such added ingredients are employed alone.
  • Utilizable potassium salts, such as potassium chloride can be included to offset possible potassium losses during therapy.
  • Such combinations include also conventional therapeutic amounts or less of hypocholesteremic agents such as the D-isomer of 3,S,3'-triiodothyronine, triiodothyropropionic acid, and thyroxine-like compounds such as sodium L-thyroxine and sodium D-thyroxine glucocorticoids such as hydrocortisone, prednisolone and 6a-methylprednisolone; anticoagulants such as heparin, 2-diphenylacetyl-l,3-indandione, polyethylene sulfonate and dicumaml or its derivatives vitamins such as nicotinic acid, vitamin B ascorbic acid and pyridoxine hydrochloride; estrogens such as estradiol; androgens such as testosterone; combinations of estrogens and androgens such as estradiol and testosterone; unsaturated fatty acids or esters such as linoleic acid or esters; antibiotics such as neomycin;
  • the novel compositions are suitably presented for ad'- ministration in unit dosage form as tablets, pills, capsules,
  • the active ingredient is mixed with a conventional non-sugar tableting component such as cornstarch, dicalcium phosphate, terra alba (calcium sulfate), talc, stearic acid, calcium stearate, gums and functionally similar materials constituting pharmaceutical diluents or carriers.
  • a conventional non-sugar tableting component such as cornstarch, dicalcium phosphate, terra alba (calcium sulfate), talc, stearic acid, calcium stearate, gums and functionally similar materials constituting pharmaceutical diluents or carriers.
  • the tablets or pills can be laminated or otherwise compounded to provide a dosage form affording the advantage of prolonged or delayed action or of predetermined successive action of the enclosed medication.
  • the tablet or pill can comprise an inner dosage and outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of. polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate phthalalte and the like.
  • sustained release coating comprises a styrene maleic acid copolymer.
  • the liquid form in which the novel compositions of this invention can be incorporated include aqueous sugarfree solutions or suspensions, emulsions or suspensions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil and the like, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include the synthetic and natural gums such as tragacanth, acacia, dextran, methylcellulose, polyvinylpyrrolidone, gelatin and the like.
  • compositions of 3-alkyl-5- alkoxymethylisoxazole In preparing pharmaceutical compositions of 3-alkyl-5- alkoxymethylisoxazole, the fact that certain of these compounds are water-insoluble, volatile liquids must be considered.
  • Appropriate oral liquid dosage forms include conventional sugar-free syrups, elixirs and non- 1aqueous solutions for use as drops or by the teaspoonful.
  • Suitable non-aqueous vehicles for oral use include the edible oils (e.g., peanut oil, cottonseed oil, coconut oil and other vegetable oils), mineral oil, glycerol, propylene glycol, polyethylene glycol 200-600, sorbitol, ethanol, or mixtures of these (e.g., equal parts of peanut oil and propylene glycol).
  • Aqueous vehicles include from about -1 to about 50% aqueous solutions of propylene glycol or ethanol or mixtures of the two comprising together the said percentages.
  • Liquid preparations for instramuscular or subcutaneous injection can be prepared as ethanolicaqueous, propylene glycol-aqueous or oil solutions (e.g., vegetable oils such as peanut oil) and in repository-type vehicles such as aluminum monostearate-peanut oil gel.
  • liquid formulations range in concentration from about 0.5 to 2040% 3-alkyl-S-alkoxymethylisoxrazo e.
  • liquid 3-alkyl-5-alkoxymethylisoxazole such as 3-methyl-5-methoxymethylisoxazole
  • solid dosage forms of liquid active ingredient require the intermediate preparation of the liquid active ingredient as discrete solid particles which can be empolyed to build the ultimate dosage form by conventional methods.
  • the liquid 3-alkyl-5-alkoxymethylisoxazole can be dissolved or dispersed in an edible oil such as a vegetable or mineral oil (in ratios of, for example,' about 1:1 to 1:200) and soft elastic capsules containingfthe oil dispersion or solution prepared for oral use.
  • Triturates of the present compounds can be made using various absorbing powders such as kaolin, magnesium carbonate, bentonite, magnesium oxide, starch, calcium carbonate, tribasic calcium phosphate, magnesium trisilicate and the like.
  • Emulsifying the liquid active ingredient preferably dissolved in a suitable .vegetable oil or mineral oil, to provide small particle sizes and then coating the said particles with a coacervate of one or more hydrophilic colloids, pharmaceutically acceptable c-opolymers, or mixtures thereof yields, on drying, free-flowing granulations which can be handled essentially as solid particles and formulated as powders, granules, tablets, hard-filled capsules and .the like.
  • a complex of a liquid 3-alkyl-5- alkoxymethylisoxazole with a pharmaceutically acceptable metal salt gives a crystalline solid which can be formulated on an equivalent weight basis into tablets, capsules, pills, powders, granules, pilules, and the like.
  • Some metal salts are less desirable than others from the standpoint of toxicity and hydroscopicity, and the zinc salts, such as zinc chloride, zinc bromide, zinc phosphate, zinc sulfate, zinc nitrate, zinc acetate, zinc carbonate, and the like, are preferred.
  • the like salts of other metals such as iron, aluminum, magnesium and calcium, can also be used.
  • metal salt complexes of 3-alkyl-5- alkoxymethylisoxazole such as 3 methyl 5 methoxymethylisoxazole
  • conventional procedures are employed to give complexes having either a 1:1 or 2:1 ratio of isoxazole to metal salt.
  • the 2:1 complex, bis-3-alky1-5- alkoxymethylisoxazole is preferred because it provides a higher proportion of isoxazole per unit weight of solid and is less hygroscopic.
  • Bringing together the desired metal salt and the desired isoxazole in a common solvent, with stirring, is sufficient to produce the desired complex in high yield.
  • a molar excess of isoxazole will give a 2:1 complex, less than a molar excess giving the 1:1 complex.
  • unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in assocition with the required pharmaceutical diluent, carrier or vehicle.
  • the specification for the novel unit dosage forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for therapeutic use, as disclosed in detail in this specification, these being features of the present invention.
  • suitable unit dosage forms are tablets, capsules, pills, powder packets, wafers, cachets, granules, non-aqueous solutions or suspensions for oral or sterile injectable use, suppositories, and segregated multiples of any of the foregoing, and other forms alluded to herein.
  • Example 1.3-methyl-5-methoxymethylisoxazole A stirred mixture of 26.0 gm. of methoxyacetylacetone, 20.8 gm. of hydroxylamine hydrochloride and 20.8 gm. of potassium carbonate was heated over an oil bath at C. for 4 hours. The mixture was allowed to cool and then was diluted with 75 ml. of water and extracted with ether. The ether extracts were dried over magnesium sulfate and concentrated. The residue was distilled at reduced pressure through a 6-inch Vigreux column to give 15.36 gm. (60.5%) of a colorless liquid boiling at 7780 C. (12 mm.). Redistillation gave an analytical sample boiling at 78 C. (12 mm.).
  • Example 2 Following the procedure of Example 1 but substituting equivalent amounts of other 1-alkoxy-4-alkylbutane- 2,4-diones for the methoxyacetylacetone therein, the alkyl groups containing 1-4 carbon atoms, gives the corresponding 3-alkyl-S-alkoxYmethylisoxazole, usually in isomeric mixture with the corresponding 5-alkyl-3-alkoxymethylisoxazole, from which the desired 3-alkyl isomer can be separated.
  • Example 4 Substituting other 3 alkyl 5 alkoxymethylisoxazoles, such as those of Example 2, for the S-methyl-S-methoxymethylisoxazole in the above reaction gives the corresponding zinc chloride complexes thereof.
  • Example 5 In foregoing Examples 3 and 4, other pharmaceutically acceptable metal salts can be substituted for the zinc chloride, the amounts being determined on a molar equivalent basis.
  • other zinc salts such as zinc bromide, zinc phosphate, zinc sulfate, zine nitrate, zinc acetate, zinc carbonate and the like can be employed.
  • Example 6 Sft gelatin capsules A batch of 1,000 soft gelatin capsules, each containing 25 mg. of 3-methyl-5methoxymethylisoxazole in mineral oil, is prepared from the following materials:
  • a uniform dispersion of the active ingredient in the mineral oil is prepared and the dispersion filled into soft gelatin capsules by conventional means.
  • One capsule is given twice a day in the treatment of diabetes.
  • Example 7 Example 7 .-N on-aqueous preparation
  • a non-aqueous liquid preparation containing 500 mg. of 3-methyl-5-methoxymethylisoxazole in each teaspoonful ml.
  • a vehicle containing 600 ml. of peanut oil and propylene glycol, q.s. to 1000 ml.
  • Example 8 Tablets A lot of 100,000 compressed tablets, each containing 100 mg. of bis-3-methy1-5-methoxymethylsioxazole zinc chloride complex, is prepared from the following ingredients:
  • ide complex 10,000 Terra alba (calcium sulfate) 25,000 Methylcellulose, U.S.P. (15 cps.) 650 Talc, bolted 4,500 Calcium stearate, fine powder 350
  • Example 9.Capsules A lot of 10,000 two-piece hard gelatin capsules for oral use, each containing 250 mg. of bis-3-methyl-5-methoxymethylisoxazole zinc chloride complex, is prepared from the following materials: Bis-3-methyl-5-methoxymethylisoxaole zinc chloride complex, 2500 gm.
  • the powdered bis-3-methyl-5-methoxymethylisoxazole zinc chloride complex is mixed with talc and starch and encapsulated in the usual manner.
  • One capsule is given once daily in the treatment of diabetes.
  • Example 10 Oil suspension An oil suspension for oral use, each 5 ml. containing 50 mg. of bis-3-methyl-S-methoxymethylisoxazole zinc chloride complex, is prepared from the following materials:
  • Example 11 In each of foregoing Examples 6 through 10 the active ingredient can be replaced by other 3-alkyl-5-alkoxymethylisoxazoles and metal complexes thereof, such as those identified in Examples 2 through 5.
  • a therapeutic composition comprising: in dosage unit form, as the primary active ingredient, from about 25 to about 500 mg. of a compound selected from the group consisting of 3-methyl-5-methoxymethylisoxazole and 3-methyl-5-methoxymethylisoxazole zinc chloride complex, in combination with a pharmaceutical carrier.
  • a method for reducing the blood sugar content of mammals comprising: administering to a mammal a 3-alkyl-5-alkoxymethylisoxazole selected from the group consisting of compounds of the formula:
  • il-MS n and 7 wherein R and R are alkyl groups of 1-4 carbon atoms, n is an integer less than 3, and MS is a pharmaceutically acceptable metal salt.
  • a method for reducing the blood sugar content of mammals comprising: administering to a mammal a compound selected from the group consisting of 3 methyl-5- methoxymethylisoxazole and 3-methyl-5-methoxymethylisoxazole zinc chloride complex.

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Description

United States Patent This invention relates to 3-alkyl-5-alkoxymethylisoxazoles and to a method for their preparation and use.
The compounds of this invention are represented by the formulas F and R (Ell L,
wherein R and R are alkyl groups of 1-4 carbon atoms, n is an integer less than 3, and MS is a metal salt. These compounds have been unexpectedly found to exhibit many times the oral hypoglycemic activity of tolbutamide in standard test animals, such as rats. The pronounced activity of these 3,5-disubstituted isoxazoles, coupled with their low order of toxicity, makes pharmaceutical compositions containing these compounds useful in reducing the blood sugar content of mammals, and in particular for administration by the preferred oral route.
Musante, Gazz. Chim. Ital. 68: 240 (1938), Chem. Centr., 193 8, II (1405), discloses the reaction of 4-imino- S-methoxy-Z-pentanone and hydroxylamine to give 5- methyl-3-methoxymethylisoxazole and observes explicitly that the presently claimed 3-methyl-5-methoxymethylisoxazole is not obtained because substitution of the imino group by the oxime radical occurs before ring formation. This reaction is as follows:
0133i lg-CHzOOH! (I) Musante also discloses the reaction of ethoxyacetylacetone with hydroxylamine as giving 5-methyl-3-ethoxymethylisoxazole, as follows:
It has now been unexpectedly found, however, that the reaction of, for example, methoxyacetylacetone with hydroxylamine gives the 3-methyl-S-methoxymethylisoxazole (III) here claimed in isomeric mixture with I above, according to the following:
CH O C 13 Patented Jan. 3, 1967 ICC a 1-a1koxy-4-alkylbutane-2,4-dione, in which the :alkyl groups contain 1-4 carbon atoms, and hydroxylamine to give an isomeric mixture of the corresponding 3-alkyl-5- alkoxymethylisoxazoles and 5-alkyl-3-alkoxymethylisoxazoles. This mixture is then separated to give the desired 3-a1kyl-S-alkoxymethylisoxazoles. The starting l-alkoxy- 4-alkylbutane-2,4-diones, such as methoxyacetylacetone, ethoxyacetylacetone, isopropoxyacetylacetone and sec-butoxyacetylacetone, are prepared by known methods from the appropriate ethylalkoxyacetate and alkylmethylketone in the presence of sodium ethoxide, according to the reaction:
in which R and R are alkyl groups containing 14 carbon atoms.
In utilizing the compositions and practicing the method of this invention, the exact schedule of administration in animals is determined individually according to the subjects age, weight, response to the medication and nature and severity of the condition being treated. For use in reducing the blood sugar content, for example, from about 25 to about 500 mg. of 3,5-disubstituted isoxazole can be administered orally as a single dose one to four times daily.
In addition to 3-alkyl-5-alkoxymethylisoxazoles as the sole active ingredient, other complementary ingredients can be included in the composition to secure advantageous combinations of properties especially adapted to individual situations in the treatment of the foregoing conditions. Thus, other hypoglycemic agents such as tolbutamide, chlorpropamide, phenformin hydrochloride, mesoxalic acid, insulin, nicotinic acid, and the like can be included in the present formulations in amounts not exceeding and preferably less than those normally employed in single unit doses where such added ingredients are employed alone. Utilizable potassium salts, such as potassium chloride, can be included to offset possible potassium losses during therapy.
Such combinations include also conventional therapeutic amounts or less of hypocholesteremic agents such as the D-isomer of 3,S,3'-triiodothyronine, triiodothyropropionic acid, and thyroxine-like compounds such as sodium L-thyroxine and sodium D-thyroxine glucocorticoids such as hydrocortisone, prednisolone and 6a-methylprednisolone; anticoagulants such as heparin, 2-diphenylacetyl-l,3-indandione, polyethylene sulfonate and dicumaml or its derivatives vitamins such as nicotinic acid, vitamin B ascorbic acid and pyridoxine hydrochloride; estrogens such as estradiol; androgens such as testosterone; combinations of estrogens and androgens such as estradiol and testosterone; unsaturated fatty acids or esters such as linoleic acid or esters; antibiotics such as neomycin; analgesics such as aspirin; compounds associated with cholesterol synthesis or metabolism such as u-phenylbutyric acid and a-p-biphenylylbutyri-c acid; lipotrophic agents such as choline and inositol; amino acids such as taurine and glycine; sterols such as sitosterol and other plant sterols; diuretics such as ethoxaz-olamide and hydrochlorothiazide; anorexigenic agents such as amphetamine; cardiovascular agents (including vasodilators and hypotensive agents), such as chlorisondamine chloride, hexamethonium chloride, and pentaerythritol tetranitrate.
In adapting the active ingredients for use in mammals, the novel compositions are suitably presented for ad'- ministration in unit dosage form as tablets, pills, capsules,
. 3 powders, wafers, cachets, granules, oral aqueous or oil dispersions, including elixirs, and the like.
For preparing solid compositions such as tablets, the active ingredient is mixed with a conventional non-sugar tableting component such as cornstarch, dicalcium phosphate, terra alba (calcium sulfate), talc, stearic acid, calcium stearate, gums and functionally similar materials constituting pharmaceutical diluents or carriers. The tablets or pills can be laminated or otherwise compounded to provide a dosage form affording the advantage of prolonged or delayed action or of predetermined successive action of the enclosed medication. For example, the tablet or pill can comprise an inner dosage and outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of. polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate phthalalte and the like. A
particularly advantageous sustained release coating comprises a styrene maleic acid copolymer.
The liquid form in which the novel compositions of this invention can be incorporated include aqueous sugarfree solutions or suspensions, emulsions or suspensions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil and the like, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include the synthetic and natural gums such as tragacanth, acacia, dextran, methylcellulose, polyvinylpyrrolidone, gelatin and the like.
In preparing pharmaceutical compositions of 3-alkyl-5- alkoxymethylisoxazole, the fact that certain of these compounds are water-insoluble, volatile liquids must be considered. Appropriate oral liquid dosage forms include conventional sugar-free syrups, elixirs and non- 1aqueous solutions for use as drops or by the teaspoonful. Suitable non-aqueous vehicles for oral use include the edible oils (e.g., peanut oil, cottonseed oil, coconut oil and other vegetable oils), mineral oil, glycerol, propylene glycol, polyethylene glycol 200-600, sorbitol, ethanol, or mixtures of these (e.g., equal parts of peanut oil and propylene glycol). Aqueous vehicles include from about -1 to about 50% aqueous solutions of propylene glycol or ethanol or mixtures of the two comprising together the said percentages. Liquid preparations for instramuscular or subcutaneous injection can be prepared as ethanolicaqueous, propylene glycol-aqueous or oil solutions (e.g., vegetable oils such as peanut oil) and in repository-type vehicles such as aluminum monostearate-peanut oil gel. In general, liquid formulations range in concentration from about 0.5 to 2040% 3-alkyl-S-alkoxymethylisoxrazo e.
Solid dosage forms of liquid 3-alkyl-5-alkoxymethylisoxazole, such as 3-methyl-5-methoxymethylisoxazole, require the intermediate preparation of the liquid active ingredient as discrete solid particles which can be empolyed to build the ultimate dosage form by conventional methods. Alternatively, the liquid 3-alkyl-5-alkoxymethylisoxazole can be dissolved or dispersed in an edible oil such as a vegetable or mineral oil (in ratios of, for example,' about 1:1 to 1:200) and soft elastic capsules containingfthe oil dispersion or solution prepared for oral use. Triturates of the present compounds can be made using various absorbing powders such as kaolin, magnesium carbonate, bentonite, magnesium oxide, starch, calcium carbonate, tribasic calcium phosphate, magnesium trisilicate and the like. Emulsifying the liquid active ingredient, preferably dissolved in a suitable .vegetable oil or mineral oil, to provide small particle sizes and then coating the said particles with a coacervate of one or more hydrophilic colloids, pharmaceutically acceptable c-opolymers, or mixtures thereof yields, on drying, free-flowing granulations which can be handled essentially as solid particles and formulated as powders, granules, tablets, hard-filled capsules and .the like.
It has been found that a complex of a liquid 3-alkyl-5- alkoxymethylisoxazole with a pharmaceutically acceptable metal salt gives a crystalline solid which can be formulated on an equivalent weight basis into tablets, capsules, pills, powders, granules, pilules, and the like. Some metal salts are less desirable than others from the standpoint of toxicity and hydroscopicity, and the zinc salts, such as zinc chloride, zinc bromide, zinc phosphate, zinc sulfate, zinc nitrate, zinc acetate, zinc carbonate, and the like, are preferred. However, the like salts of other metals, such as iron, aluminum, magnesium and calcium, can also be used.
In preparing the metal salt complexes of 3-alkyl-5- alkoxymethylisoxazole, such as 3 methyl 5 methoxymethylisoxazole, conventional procedures are employed to give complexes having either a 1:1 or 2:1 ratio of isoxazole to metal salt. The 2:1 complex, bis-3-alky1-5- alkoxymethylisoxazole, is preferred because it provides a higher proportion of isoxazole per unit weight of solid and is less hygroscopic. Bringing together the desired metal salt and the desired isoxazole in a common solvent, with stirring, is sufficient to produce the desired complex in high yield. A molar excess of isoxazole will give a 2:1 complex, less than a molar excess giving the 1:1 complex.
The term unit dosage form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in assocition with the required pharmaceutical diluent, carrier or vehicle. The specification for the novel unit dosage forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for therapeutic use, as disclosed in detail in this specification, these being features of the present invention. Examples of suitable unit dosage forms, as heretofore described, are tablets, capsules, pills, powder packets, wafers, cachets, granules, non-aqueous solutions or suspensions for oral or sterile injectable use, suppositories, and segregated multiples of any of the foregoing, and other forms alluded to herein.
The following examples illustrate the best mode contemplated for carrying out the invention, but such examples are not to be construed as limiting the scope thereof.
Example 1.3-methyl-5-methoxymethylisoxazole A stirred mixture of 26.0 gm. of methoxyacetylacetone, 20.8 gm. of hydroxylamine hydrochloride and 20.8 gm. of potassium carbonate was heated over an oil bath at C. for 4 hours. The mixture was allowed to cool and then was diluted with 75 ml. of water and extracted with ether. The ether extracts were dried over magnesium sulfate and concentrated. The residue was distilled at reduced pressure through a 6-inch Vigreux column to give 15.36 gm. (60.5%) of a colorless liquid boiling at 7780 C. (12 mm.). Redistillation gave an analytical sample boiling at 78 C. (12 mm.).
Analysis.Calculated for C H NO C, 56.68; H, 7.14; N, 11.02. Found: C, 56.82; H, 7.42; N, 10.29.
The analytical sample above was further purified by vapor phase chromatography to give two distinct fractions. By nuclear magnetic resonance one fraction was identified as 3-methyl-S-methoxymethylisoxazole and the other as 5- methyl-3-methoxymethylisoxazole, each essentially free of the other isomer.
Example 2 Following the procedure of Example 1 but substituting equivalent amounts of other 1-alkoxy-4-alkylbutane- 2,4-diones for the methoxyacetylacetone therein, the alkyl groups containing 1-4 carbon atoms, gives the corresponding 3-alkyl-S-alkoxYmethylisoxazole, usually in isomeric mixture with the corresponding 5-alkyl-3-alkoxymethylisoxazole, from which the desired 3-alkyl isomer can be separated. By this method there is prepared, for example, 3 methyl 5 ethoxymethylisoxazole, 3 methyl 5- isopropoxymethylisoxazole, 3 methyl 5 secbutoxymethylisoxazole, 3 ethyl 5 methoxymethylisoxazole, 3 ethyl 5 ethoxymethylisoxazole, 3 ethyl 5 isopropoxymethylisoxazole, 3 ethyl 5 sec butoxymethylisoxazole and the corresponding 3propyland 3-sec-butyl derivatives of the foregoing compounds.
Example 3.Bis-3-methyl-5-m'eth0xymethylisoxaz0le zinc chloride complex Example 4 Substituting other 3 alkyl 5 alkoxymethylisoxazoles, such as those of Example 2, for the S-methyl-S-methoxymethylisoxazole in the above reaction gives the corresponding zinc chloride complexes thereof.
Example 5 In foregoing Examples 3 and 4, other pharmaceutically acceptable metal salts can be substituted for the zinc chloride, the amounts being determined on a molar equivalent basis. In particular, other zinc salts, such as zinc bromide, zinc phosphate, zinc sulfate, zine nitrate, zinc acetate, zinc carbonate and the like can be employed.
Example 6.- Sft gelatin capsules A batch of 1,000 soft gelatin capsules, each containing 25 mg. of 3-methyl-5methoxymethylisoxazole in mineral oil, is prepared from the following materials:
Gm. 3-methyl-S-methoxymethylisoxazole 25 Mineral oil, U.S.P. 100
A uniform dispersion of the active ingredient in the mineral oil is prepared and the dispersion filled into soft gelatin capsules by conventional means.
One capsule is given twice a day in the treatment of diabetes.
Example 7 .-N on-aqueous preparation One thousand milliliters of a non-aqueous liquid preparation containing 500 mg. of 3-methyl-5-methoxymethylisoxazole in each teaspoonful ml.) is prepared by dispersing 100 gm. of active ingredient in a vehicle containing 600 ml. of peanut oil and propylene glycol, q.s. to 1000 ml.
Example 8.Tablets A lot of 100,000 compressed tablets, each containing 100 mg. of bis-3-methy1-5-methoxymethylsioxazole zinc chloride complex, is prepared from the following ingredients:
Bis-3 -methyl-5-methoxymethylisoxazole zinc chlor- Gm.
ide complex 10,000 Terra alba (calcium sulfate) 25,000 Methylcellulose, U.S.P. (15 cps.) 650 Talc, bolted 4,500 Calcium stearate, fine powder 350 Example 9.Capsules A lot of 10,000 two-piece hard gelatin capsules for oral use, each containing 250 mg. of bis-3-methyl-5-methoxymethylisoxazole zinc chloride complex, is prepared from the following materials: Bis-3-methyl-5-methoxymethylisoxaole zinc chloride complex, 2500 gm.
The powdered bis-3-methyl-5-methoxymethylisoxazole zinc chloride complex is mixed with talc and starch and encapsulated in the usual manner.
One capsule is given once daily in the treatment of diabetes.
Example 10.Oil suspension An oil suspension for oral use, each 5 ml. containing 50 mg. of bis-3-methyl-S-methoxymethylisoxazole zinc chloride complex, is prepared from the following materials:
Saccharin sodium gm 0.5 Cyclamate sodium gm 0.1 Bis 3 methyl 5 methoxymethylisoxazole zinc chloride complex gm Benzoic acid, powder gm 0.5 Methylparaben gm 0.5 Butylated hydroxyanisole gm 0.05 Oil of orange ml 1 Aluminum monostearate-corn oil gel, q.s ml 10,000 One teaspoonful (5 mil.) is given twice daily in the treatment of diabetes.
Example 11 In each of foregoing Examples 6 through 10 the active ingredient can be replaced by other 3-alkyl-5-alkoxymethylisoxazoles and metal complexes thereof, such as those identified in Examples 2 through 5.
What is claimed is:
1. A therapeutic composition comprising: in dosage unit form, as the primary active ingredient, from about 25 to about 500 mg. of a compound selected from the group consisting of 3-methyl-5-methoxymethylisoxazole and 3-methyl-5-methoxymethylisoxazole zinc chloride complex, in combination with a pharmaceutical carrier.
2. A method for reducing the blood sugar content of mammals comprising: administering to a mammal a 3-alkyl-5-alkoxymethylisoxazole selected from the group consisting of compounds of the formula:
il-MS n and 7 wherein R and R are alkyl groups of 1-4 carbon atoms, n is an integer less than 3, and MS is a pharmaceutically acceptable metal salt.
3. A method for reducing the blood sugar content of mammals comprising: administering to a mammal a compound selected from the group consisting of 3 methyl-5- methoxymethylisoxazole and 3-methyl-5-methoxymethylisoxazole zinc chloride complex.
References Cited by the Examiner UNITED STATES PATENTS 2,260,256 10/1941 Lippincott 260--307 8 Caspe 167-65 Gardner 260-307 Wright 167-65 Kano 260--307 Heifer 260299 JULIAN S. LEVITT, Primary Examiner. FRANK CACCIAPAGLIA, m, s. ROSEN,
Examiners.
10 M. J. COHEN, J. D. GOLDBERG, Assistant Examiners.

Claims (1)

  1. 3. A METHOD FOR REDUCING THE BLOOD SUGAR CONTENT OF MAMMALS COMPRISING: ADMINISTERING TO A MAMMAL A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3-METHYL-5METHOXYMETHYLISOXAZOLE AND 3-METHYL-5-METHOXYMETHYLISOXAZOLE ZINC CHLORIDE COMPLEX.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3435047A (en) * 1964-09-14 1969-03-25 Sankyo Co Process for preparing 3-aminoisoxazole derivatives
US4657914A (en) * 1982-04-30 1987-04-14 Farmitalia Carlo Erba S.P.A. Ergoline derivatives
US20040077620A1 (en) * 2001-01-31 2004-04-22 Yoshitane Kojima Hypoglycemic agent

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2260256A (en) * 1940-07-08 1941-10-21 Commercial Solvents Corp Production of dioximes and isoxazoles
US2793977A (en) * 1951-08-31 1957-05-28 Caspe Saul Compositions and method for reducing blood sugar concentration
US3047581A (en) * 1961-01-16 1962-07-31 Hoffmann La Roche Substituted isoxazolyl compounds
US3063903A (en) * 1961-03-29 1962-11-13 Upjohn Co Novel n-arylsulfonyl n'-(cyclicamino) ureas and oral antidiabetic compositions containing said novel compounds
US3073839A (en) * 1958-09-20 1963-01-15 Shionogi & Co Novel process for preparing 3-aminoisoxazole
US3090788A (en) * 1960-11-02 1963-05-21 Hoffmann La Roche Substituted isoxazole carboxamide compounds

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2260256A (en) * 1940-07-08 1941-10-21 Commercial Solvents Corp Production of dioximes and isoxazoles
US2793977A (en) * 1951-08-31 1957-05-28 Caspe Saul Compositions and method for reducing blood sugar concentration
US3073839A (en) * 1958-09-20 1963-01-15 Shionogi & Co Novel process for preparing 3-aminoisoxazole
US3090788A (en) * 1960-11-02 1963-05-21 Hoffmann La Roche Substituted isoxazole carboxamide compounds
US3047581A (en) * 1961-01-16 1962-07-31 Hoffmann La Roche Substituted isoxazolyl compounds
US3063903A (en) * 1961-03-29 1962-11-13 Upjohn Co Novel n-arylsulfonyl n'-(cyclicamino) ureas and oral antidiabetic compositions containing said novel compounds

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3435047A (en) * 1964-09-14 1969-03-25 Sankyo Co Process for preparing 3-aminoisoxazole derivatives
US4657914A (en) * 1982-04-30 1987-04-14 Farmitalia Carlo Erba S.P.A. Ergoline derivatives
US20070155657A1 (en) * 2001-01-13 2007-07-05 Japan Science And Technology Corporation Hypoglycemic agent
US20040077620A1 (en) * 2001-01-31 2004-04-22 Yoshitane Kojima Hypoglycemic agent
US20050130880A1 (en) * 2001-01-31 2005-06-16 Yoshitane Kojima Hypoglycemic agent
EP1364647A4 (en) * 2001-01-31 2006-04-05 Japan Science & Tech Agency HYPOGLYCEMIC AGENT
US20070155655A1 (en) * 2001-01-31 2007-07-05 Japan Science And Technology Corporation Hypoglycemic agent
US20070155656A1 (en) * 2001-01-31 2007-07-05 Japan Science And Technology Corporation Hypoglycemic agent
EP1897541A3 (en) * 2001-01-31 2008-05-28 Japan Science and Technology Agency Hypoglycemic agent
EP1900366A3 (en) * 2001-01-31 2008-06-25 Japan Science and Technology Agency Hypoglycemic agent
EP1900367A3 (en) * 2001-01-31 2008-07-02 Japan Science and Technology Agency Hypoglycemic agent
EP1905438A3 (en) * 2001-01-31 2008-07-02 Japan Science and Technology Agency Hypoglycemic agent

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